The invention is directed to novel xcex22 adrenergic receptor agonists. The invention is also directed to pharmaceutical compositions comprising such compounds, methods of using such compounds to treat diseases associated with xcex22 adrenergic receptor activity, and processes and intermediates useful for preparing such compounds.
xcex22 adrenergic receptor agonists are recognized as effective drugs for the treatment of pulmonary diseases such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema). xcex22 adrenergic receptor agonists are also useful for treating pre-term labor, and are potentially useful for treating neurological disorders and cardiac disorders. In spite of the success that has been achieved with certain xcex22 adrenergic receptor agonists, current agents possess less than desirable potency, selectivity, speed of onset, and/or duration of action. Thus, there is a need for additional xcex22 adrenergic receptor agonists having improved properties. Preferred agents may possess, among other properties, improved duration of action, potency, selectivity, and/or onset.
The invention provides novel compounds that possess xcex22 adrenergic receptor agonist activity. Accordingly, this invention provides compounds of formula (I): 
wherein:
each of R1-R5 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and Ra;
or R1 and R2, R2 and R3, R3 and R4, or R4 and R5 are joined together to form a group selected from the group consisting of xe2x80x94C(Rd)xe2x95x90C(Rd)C(xe2x95x90O)NRdxe2x80x94, xe2x80x94CRdRdxe2x80x94CRdRdxe2x80x94C(xe2x95x90O)NRdxe2x80x94, xe2x80x94NRdC(xe2x95x90O)C(Rd)xe2x95x90C(Rd)xe2x80x94, xe2x80x94NRdC(xe2x95x90O)CRdRdxe2x80x94CRdRdxe2x80x94, xe2x80x94NRdC(xe2x95x90O)Sxe2x80x94, xe2x80x94SC(xe2x95x90O)NRdxe2x80x94, xe2x80x94(CRdRd)pxe2x80x94, xe2x80x94S(CRdRd)qxe2x80x94, xe2x80x94(CRdRd)qSxe2x80x94, xe2x80x94S(CRdRd)rOxe2x80x94, xe2x80x94O(CRdRd)rSxe2x80x94, and xe2x80x94NHC(Rj)xe2x95x90C(Rk)xe2x80x94;
R6 is hydrogen, alkyl, or alkoxy;
R7 is hydrogen or alkyl;
R8 is hydrogen or alkyl; or R8 together with R9 is xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94;
R9 is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, and Ra, or R9 together with R8 is xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94;
R10 is hydrogen or alkyl;
each R11, R12, and R13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, xe2x80x94NO2, halo, xe2x80x94NRdRe, xe2x80x94C(xe2x95x90O)Rd, xe2x80x94CO2Rd, xe2x80x94OC(xe2x95x90O)Rd, xe2x80x94CN, xe2x80x94C(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)Re, xe2x80x94OC(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)ORe, xe2x80x94NRdC(xe2x95x90O)NRdRe, xe2x80x94ORd, xe2x80x94S(O)mRd, xe2x80x94NRdxe2x80x94NRdxe2x80x94C(xe2x95x90O)Rd, xe2x80x94NRdNxe2x95x90CRdRd, xe2x80x94N(NRdRe)Rd, and xe2x80x94S(O)2NRdRe;
or R11 and R12 together with the atoms to which they are attached form a fused benzo ring, which benzo ring can optionally be substituted with 1, 2, 3, or 4 Rc;
or R11 and R12 together with the atoms to which they are attached form a heterocyclic ring;
wherein for R1-R6, R9, and R11-R13, each alkyl, alkenyl, and alkynyl is optionally substituted with Rm, or with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from Rb; for R1-R6, R9, and R11-R13 each aryl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rc, and for R1-R6, R9, and R11-R13 each cycloalkyl and heterocyclic ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rb and Rc;
each Ra is independently xe2x80x94ORd, xe2x80x94NO2, halo, xe2x80x94S(O)mRd, xe2x80x94S(O)2ORd, xe2x80x94S(O)mNRdRe, xe2x80x94NRdRe, xe2x80x94O(CRfRg)nNRdRe, xe2x80x94C(xe2x95x90O)Rd, xe2x80x94CO2Rd, xe2x80x94CO2(CRfRg)nxe2x80x94CONRdRe, xe2x80x94OC(xe2x95x90O)Rd, xe2x80x94CN, xe2x80x94C(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)Re, xe2x80x94OC(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)ORe, xe2x80x94NRdC(xe2x95x90O)NRdRe, xe2x80x94CRd(xe2x95x90Nxe2x80x94ORe), xe2x80x94CF3, or xe2x80x94OCF3;
each Rb is independently Ra, oxo, or xe2x95x90Nxe2x80x94ORe;
each Rc is independently Ra, alkyl, alkenyl, or alkynyl; wherein each alkyl, alkenyl and alkynyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rb;
each Rd and Re is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from Rh; or Rd and Re together with the atoms to which they are attached form a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
each Rf and Rg is independently hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein each alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rh; or Rf and Rg together with the carbon atom to which they are attached form a ring having from 5 to 7 ring atoms, wherein the ring optionally contains 1 or 2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
each Rh is independently halo, C1-8alkyl, C1-8alkoxy, xe2x80x94Sxe2x80x94C1-8alkyl, aryl, (aryl)-C1-6alkyl, (aryl)-C1-8alkoxy, heteroaryl, (heteroaryl)-C1-6alkyl, (heteroaryl)-C1-8alkoxy, hydroxy, amino, xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94OC(xe2x95x90O)C1-6alkyl, xe2x80x94C(xe2x95x90O)C1-6alkyl, xe2x80x94C(xe2x95x90O)OC1-6alkyl, xe2x80x94NHC(xe2x95x90O)C1-6alkyl, xe2x80x94C(xe2x95x90O)NHC1-6alkyl, carboxy, nitro, xe2x80x94CN, or xe2x80x94CF3;
Rj and Rk together with the carbon atoms to which they are attached form a phenyl ring that is optionally substituted with 1, 2, 3, or 4 Rc;
each Rm is independently aryl, heteroaryl, cycloalkyl or heterocyclyl; wherein each aryl or heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of Rc, and wherein each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents selected from Rb;
m is 0, 1, or 2;
n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
p is 3, 4, or 5;
q is 2, 3, or 4;
r is 1, 2, or 3;
w is 0, 1, 2, 3, or 4;
or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof.
The invention also provides compounds of formula (II): 
wherein:
R4 is xe2x80x94CH2OH or xe2x80x94NHCHO and R5 is hydrogen; or R4 and R5 taken together are xe2x80x94NHC(xe2x95x90O)CHxe2x95x90CHxe2x80x94;
R11 is phenyl or heteroaryl, wherein each phenyl is optionally substituted with 1 or 2 substituents selected from halo, xe2x80x94ORd, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO2Rd, xe2x80x94C(xe2x95x90O)Rd, xe2x80x94C(xe2x95x90O)NRdRe, and C1-3alkyl, wherein C1-3alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and each Rd and Re is independently hydrogen or C1-3alkyl; and wherein each heteroaryl is optionally substituted with 1 or 2 C1-3alkyl substituents; and
R12 is hydrogen or xe2x80x94OC1-6alkyl;
or a pharmaceutically-acceptable salt or solvate or stereoisomer thereof.
The invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically-acceptable carrier.
The invention also provides a method of treating a disease or condition associated with xcex22 adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation) in a mammal, comprising administering to the mammal, a therapeutically effective amount of a compound of the invention.
The invention also provides a method of treating a disease or condition associated with xcex22 adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation) in a mammal, comprising administering to the mammal, a therapeutically effective amount of a pharmaceutical composition of the invention.
This invention also provides a method of modulating a xcex22 adrenergic receptor, the method comprising stimulating a xcex22 adrenergic receptor with a modulatory amount of a compound of the invention.
In separate and distinct aspects, the invention also provides synthetic processes and novel intermediates, including compounds of formulas (III), (IV), and (VII) described herein, which are useful for preparing compounds of the invention.
The invention also provides a compound of the invention as described herein for use in medical therapy, as well as the use of a compound of the invention in the manufacture of a formulation or medicament for treating a disease or condition associated with xcex22 adrenergic receptor activity (e.g. a pulmonary disease, such as asthma or chronic obstructive pulmonary disease, pre-term labor, a neurological disorder, a cardiac disorder, or inflammation) in a mammal.
When describing the compounds, compositions and methods of the invention, the following terms have the following meanings, unless otherwise indicated.
The term xe2x80x9calkylxe2x80x9d refers to a monovalent saturated hydrocarbon group which may be linear or branched or combinations thereof. Such alkyl groups preferably contain from 1 to 20 carbon atoms; more preferably, from 1 to 8 carbon atoms; and still more preferably, from 1 to 4 carbon atoms. Representative alkyl groups include, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
The term xe2x80x9calkenylxe2x80x9d refers to a monovalent unsaturated hydrocarbon group containing at least one carbon-carbon double bond, typically 1 or 2 carbon-carbon double bonds, and which may be linear or branched or combinations thereof. Such alkenyl groups preferably contain from 2 to 20 carbon atoms; more preferably from 2 to 8 carbon atoms; and still more preferably, from 2 to 4 carbon atoms. Representative alkenyl groups include, by way of example, vinyl, allyl, isopropenyl, but-2-enyl, n-pent-2-enyl, n-hex-2-enyl, n-hept-2-enyl, n-oct-2-enyl, n-non-2-enyl, n-dec-4-enyl, n-dec-2,4-dienyl and the like.
The term xe2x80x9calkynylxe2x80x9d refers to a monovalent unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, typically 1 carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Such alkynyl groups preferably contain from 2 to 20 carbon atoms; more preferably from 2 to 8 carbon atoms; and still more preferably, from 2 to 4 carbon atoms. Representative alkynyl groups include, by way of example, ethynyl, propargyl, but-2-ynyl and the like.
The term xe2x80x9calkoxyxe2x80x9d refers to a group of the formula xe2x80x94OR, where R is an alkyl group as defined herein. Representative alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy and the like.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a monovalent saturated carbocyclic group which may be monocyclic or multicyclic. Each ring of such cycloalkyl groups preferably contains from 3 to 10 carbon atoms. This term also includes cycloalkyl groups fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic (cycloalkyl) portion of the group. Representative cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1,2,3,4-tetrahydronaphth-2-yl, decahydronaphthyl, indan-1-yl, adamantyl, norbornyl and the like.
The term xe2x80x9carylxe2x80x9d refers to a monovalent carbocyclic group which may be monocyclic or multicyclic (i.e., fused) wherein at least one ring is aromatic. Such aryl groups preferably contain from 6 to 20 carbon atoms; more preferably, from 6 to 10 carbon atoms. This term includes multicyclic carbocyclic ring systems wherein one or more rings are not aromatic, provided the point of attachment is on an aromatic ring. Representative aryl groups include, by way of example, phenyl, napthyl, azulenyl, indan-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, and the like.
The term xe2x80x9cheteroarylxe2x80x9d refers to a monovalent aromatic group that contains at least one heteroatom, preferably 1 to 4 heteroatoms, selected from N, S and O, and which may be monocyclic or multicyclic (i.e., fused). Such heteroaryl groups preferably contain from 5 to 20 atoms; more preferably, from 5 to 10 atoms. This term also includes heteroaryl groups fused to a cycloalkyl or aryl group, in which the point of attachment is on the aromatic (heteroaryl) portion of the group. Representative heteroaryl groups include, by way of example, pyrroyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl (or, equivalently, pyridinyl), oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, quinolyl, indolyl, isoquinolyl and the like.
The term xe2x80x9cheterocyclylxe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d refers to a saturated or partially unsaturated cyclic non-aromatic group, which may be monocyclic or multicyclic (i.e., fused or bridged), and which contains at least one heteroatom, preferably 1 to 4 heteroatoms, selected from N(X), S and O, wherein each X is independently hydrogen or alkyl. Such heterocyclyl groups preferably contain from 3 to 20 atoms; more preferably, from 3 to 10 atoms. This term also includes such a heterocyclyl group fused to one or more cycloalkyl, aryl, or heteroaryl groups. The point of attachment of the heterocyclyl group may be any carbon or nitrogen atom in a heterocyclyl, cycloalkyl, aryl or heteroaryl portion of the group. Representative heterocyclyl groups include, by way of example, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, morpholinyl, indolin-3-yl, 2-imidazolinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, quinuclidinyl, 2-oxobenzopyran, and the like.
The term xe2x80x9chaloxe2x80x9d refers to a fluoro, chloro, bromo or iodo.
The term xe2x80x9coxoxe2x80x9d refers to a group of the formula xe2x95x90O.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to an amount sufficient to effect treatment when administered to a patient in need of treatment.
The term xe2x80x9ctreatmentxe2x80x9d as used herein refers to the treatment of a disease or medical condition in a patient, such as a mammal (particularly a human), and includes:
(a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient;
(b) ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient;
(c) suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient, or
(d) alleviating the symptoms of the disease or medical condition in a patient.
The phrase xe2x80x9cdisease or condition associated with xcex22 adrenergic receptor activityxe2x80x9d includes all disease states and/or conditions that are acknowledged now, or that are found in the future, to be associated with xcex22 adrenergic receptor activity. Such disease states include, but are not limited to, bronchoconstrictive or pulmonary diseases, such as asthma and chronic obstructive pulmonary disease (including chronic bronchitis and emphysema), as well as neurological disorders and cardiac disorders. xcex22 Adrenergic receptor activity is also known to be associated with pre-term labor (see, for example, U.S. Pat. No. 5,872,126) and some types of inflammation (see, for example, WO 99/30703 and U.S. Pat. No. 5,290,815).
The term xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d refers to a salt prepared from a base or acid which is acceptable for administration to a patient, such as a mammal. Such salts can be derived from pharmaceutically-acceptable inorganic or organic bases and from pharmaceutically-acceptable inorganic or organic acids.
Salts derived from pharmaceutically-acceptable acids include acetic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic (1-hydroxy-2-naphthoic acid) and the like. Particularly preferred are salts derived from fumaric, hydrobromic, hydrochloric, acetic, sulfuric, phosphoric, methanesulfonic, p-toluenesulfonic, xinafoic, tartaric, citric, malic, maleic, succinic, and benzoic acids.
Salts derived from pharmaceutically-acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occuring amines and the like, such as arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
The term xe2x80x9csolvatexe2x80x9d refers to a complex or aggregate formed by one or more molecules of a solute, i.e. a compound of the invention or a pharmaceutically-acceptable salt thereof, and one or more molecules of a solvent. Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. Representative solvents include by way of example, water, methanol, ethanol, isopropanol, acetic acid, and the like. When the solvent is water, the solvate formed is a hydrate.
The term xe2x80x9cleaving groupxe2x80x9d refers to a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
The term xe2x80x9camino-protecting groupxe2x80x9d refers to a protecting group suitable for preventing undesired reactions at an amino nitrogen. Representative amino-protecting groups include, but are not limited to, formyl; acyl groups, for example alkanoyl groups, such as acetyl; alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl groups, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl groups, such as benzyl (Bn), trityl (Tr), and 1,1-di-(4xe2x80x2-methoxyphenyl)methyl; silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
The term xe2x80x9chydroxy-protecting groupxe2x80x9d refers to a protecting group suitable for preventing undesired reactions at a hydroxy group. Representative hydroxy-protecting groups include, but are not limited to, alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, for example alkanoyl groups, such as acetyl; arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.
Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.
A specific value for R1 is hydrogen.
A specific value for R2 is hydrogen.
A specific value for R3 is hydroxy.
A specific value for R4 is xe2x80x94CH2OH or xe2x80x94NHCHO.
A specific value for R5 is hydrogen.
A specific value for R4 and R5 together are xe2x80x94NHC(xe2x95x90O)CHxe2x95x90CHxe2x80x94 or xe2x80x94SC(xe2x95x90O)NHxe2x80x94.
A specific value for R6 is hydrogen.
A specific value for R7 is hydrogen.
A specific value for R8 is hydrogen.
A specific value for w is 0.
Another specific value for w is 1 or 2.
A specific value for R9 together with R8 is xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94.
A specific value for R10 is hydrogen.
Another specific value for R10 is alkyl.
A specific value for R11 is hydrogen.
Another specific value for R11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, xe2x80x94NO2, halo, xe2x80x94NRdRe, xe2x80x94C(xe2x95x90O)Rd, xe2x80x94CO2Rd, xe2x80x94OC(xe2x95x90O)Rd, xe2x80x94CN, xe2x80x94C(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)Re, xe2x80x94OC(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)ORe, xe2x80x94NRdC(xe2x95x90O)NRdRe, xe2x80x94ORd, xe2x80x94S(O)mRd, xe2x80x94NRdxe2x80x94NRd C(xe2x95x90O)Rd, xe2x80x94NRdxe2x80x94Nxe2x95x90CRdRd, xe2x80x94N(NRdRe)Rd, or xe2x80x94S(O)2NRdRe.
Another specific value for R11 is hydrogen, alkyl, heterocyclyl, xe2x80x94ORd, xe2x80x94S(O)mRd, or xe2x80x94S(O)2NRdRe.
Another specific value for R11 is heterocyclyl, xe2x80x94ORd, xe2x80x94S(O)mRd, or xe2x80x94S(O)2NRdRe.
Another specific value for R11 is xe2x80x94ORd.
Another specific value for R11 is xe2x80x94S(O)mRd.
A specific value for R12 is hydrogen.
Another specific value for R12 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, xe2x80x94NO2, halo, xe2x80x94NRdRe, xe2x80x94C(xe2x95x90O)Rd, xe2x80x94CO2Rd, xe2x80x94OC(xe2x95x90O)Rd, xe2x80x94CN, xe2x80x94C(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)Re, xe2x80x94OC(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)ORe, xe2x80x94NRdC(xe2x95x90O)NRdRe, xe2x80x94ORd, xe2x80x94S(O)mRd, xe2x80x94NRdxe2x80x94NRdxe2x80x94C(xe2x95x90O)Rd, xe2x80x94NRdxe2x80x94Nxe2x95x90CRdRd, xe2x80x94N(NRdRe)Rd, or xe2x80x94S(O)2NRdRe.
Another specific value for R12 is hydrogen, alkyl, heterocyclyl, xe2x80x94ORd, xe2x80x94S(O)mRd, or xe2x80x94S(O)2NRdRe.
A specific value for R12 is heterocyclyl, xe2x80x94ORd, xe2x80x94S(O)mRd, or xe2x80x94S(O)2NRdRe.
Another specific value for R12 is xe2x80x94ORd.
Another specific value for R12 is xe2x80x94S(O)mRd.
Another specific value for R12 is xe2x80x94S(O)2NRdRe.
A specific value for R13 is hydrogen.
Another specific value for R13 is alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, xe2x80x94NO2, halo, xe2x80x94NRdRe, xe2x80x94C(xe2x95x90O)Rd, xe2x80x94CO2Rd, xe2x80x94OC(xe2x95x90O)Rd, xe2x80x94CN, xe2x80x94C(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)Re, xe2x80x94OC(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)ORe, xe2x80x94NRdC(xe2x95x90O)NRdRe, xe2x80x94ORd, xe2x80x94S(O)Rd, xe2x80x94NRdxe2x80x94NRdxe2x80x94C(xe2x95x90O)Rd, xe2x80x94NRdxe2x80x94Nxe2x95x90CRdRd, xe2x80x94N(NRdRe)Rd, or xe2x80x94S(O)2NRdRe.
Another specific value for R13 is hydrogen, alkyl, heterocyclyl, xe2x80x94ORd, xe2x80x94S(O)mRd, or xe2x80x94S(O)2NRdRe.
Another specific value for R13 is heterocyclyl, xe2x80x94ORd, xe2x80x94S(O)mRd, or xe2x80x94S(O)2NRdRe.
A specific value for R13 is xe2x80x94ORd.
A specific value for R13 is xe2x80x94S(O)mRd.
A specific group of compounds of the invention are compounds wherein each of R1-R4 is independently selected from the group consisting of hydrogen, fluoro, chloro, amino, hydroxy, N,N-dimethylaminocarbonyloxy, xe2x80x94CH2OH, and xe2x80x94NHCHO, and R5 is hydrogen; or R1 is hydrogen, R2 is hydrogen, R3 is hydroxy, and R4 and R5 together are xe2x80x94NHC(xe2x95x90O)CHxe2x95x90CHxe2x80x94 or xe2x80x94SC(xe2x95x90O)NHxe2x80x94.
A specific group of compounds of the invention are compounds wherein R1 is hydrogen; R2 is chloro; R3 is amino; R4 is chloro; and R5 is hydrogen.
A specific group of compounds of the invention are compounds wherein R1 is hydrogen; R2 is N,N-dimethylaminocarbonyloxy; R3 is hydrogen; R4 is N,N-dimethylaminocarbonyloxy; and R5 is hydrogen.
A specific group of compounds of the invention are compounds wherein R1 is hydrogen, fluoro, or chloro; R2 is hydroxy; R3 is hydrogen; R4 is hydroxy; and R5 is hydrogen.
A specific group of compounds of the invention are compounds wherein R1 is chloro; R2 is hydrogen; R3 is hydroxy; R4 is hydrogen; and R5 is hydrogen.
A specific group of compounds of the invention are compounds wherein R1 is hydrogen; R2 is hydrogen; R3 is hydroxy; R4 is xe2x80x94CH2OH; and R5 is hydrogen.
A specific group of compounds of the invention are compounds wherein R1 is hydrogen; R2 is hydrogen; R3 is hydroxy; R4 is xe2x80x94NHCHO; and R5 is hydrogen.
A specific group of compounds of the invention are compounds wherein R1 is hydrogen; R2 is hydrogen; R3 is hydroxy; and R4and R5 together are xe2x80x94NHC(xe2x95x90O)CHxe2x95x90CHxe2x80x94.
A specific group of compounds of the invention are compounds wherein R1 is hydrogen; R2 is hydrogen; R3 is hydroxy; and R4 and R5 together are xe2x80x94SC(xe2x95x90O)NHxe2x80x94.
A specific group of compounds of the invention are compounds wherein R11 is hydrogen, R12 is xe2x80x94SRd; R13 is hydrogen; and Rd is alkyl, aryl, or heteroaryl.
A specific group of compounds of the invention are compounds wherein R11 is xe2x80x94SRd, R12 is hydrogen; R13 is hydrogen; and Rd is alkyl, aryl, heteroaryl.
When part of the group xe2x80x94SRd, a specific value for Rd is alkyl.
When part of the group xe2x80x94SRd, another specific value for Rd is C1-6alkyl.
When part of the group xe2x80x94SRd, another specific value for Rd is C1-3alkyl.
When part of the group xe2x80x94SRd, another more specific value for Rd is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C1-6alkoxy, hydroxy, amino, xe2x80x94N(C1-6alkyl)2, nitro, xe2x80x94CN, and xe2x80x94CF3.
When part of the group xe2x80x94SRd, another more specific value for Rd is phenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from fluoro and C1-3alkyl.
A specific group of compounds of the invention are compounds wherein R11 or R12 is methylthio, 2-methylphenylthio, 4-methyl-2-pyrimidylthio, 4-fluorophenylthio, or 4-methylphenylthio.
A specific group of compounds of the invention are compounds wherein R11 is hydrogen or alkyl, R12 is xe2x80x94SO2NRdRe; and R13 is hydrogen.
A specific group of compounds of the invention are compounds wherein R11 is xe2x80x94SO2NRdRe, R12 is hydrogen or alkyl; and R13 is hydrogen.
When part of the group xe2x80x94SO2NRdRe, a specific value for Rd is alkyl, aryl, or heteroaryl; and for Re is hydrogen, alkyl, aryl, or heteroaryl; wherein each alkyl, aryl, or heteroaryl, is optionally substituted with one or more (e.g. 1, 2, 3, or 4) substituents independently selected from Rh; or Rd and Re together with the nitrogen atom to which they are attached is a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen.
When part of the group xe2x80x94SO2NRdRe, a specific value for Rd and Re independently is hydrogen, alkyl, aryl, or heteroaryl; wherein each alkyl, aryl, or heteroaryl, is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rh.
As a substituent as part of the group xe2x80x94SO2NRdRe, a specific value for Rh is halo, C1-8alkyl, C1-8alkoxy, xe2x80x94Sxe2x80x94C1-8alkyl, aryl, hydroxy, amino, xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94OC(xe2x95x90O)C1-6alkyl, xe2x80x94C(xe2x95x90O)C1-6alkyl, xe2x80x94C(xe2x95x90O)OC1-6alkyl, xe2x80x94NHC(xe2x95x90O)C1-6alkyl, xe2x80x94C(xe2x95x90O)NHC1-6alkyl, carboxy, nitro, xe2x80x94CN, or xe2x80x94CF3.
Another specific value for Rh in the above context is halo, C1-6alkyl, C1-6alkoxy, or xe2x80x94CF3.
When part of the group xe2x80x94SO2NRdRe, a specific value for Rd and Re together with the nitrogen atom to which they are attached is a heterocyclic ring having from 5 to 7 ring atoms, wherein the heterocyclic ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, sulfur or nitrogen.
When part of the group xe2x80x94SO2NRdRe, a specific value for Rd and Re independently is alkyl; wherein each alkyl is optionally substituted with 1 or 2 alkoxy substituents.
When part of the group xe2x80x94SO2NRdRe, a specific value for Rd or Re is phenyl, or naphthyl; wherein each phenyl and naphthyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C1-6alkoxy, and xe2x80x94CF3.
When part of the group xe2x80x94SO2NRdRe, a specific value for Rd or Re is heteroaryl; wherein each heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C1-6alkoxy, and xe2x80x94CF3. Preferably heteroaryl is pyridyl, pyrimidyl, or thiazolyl.
A preferred group of compounds are compounds wherein R11 or R12 is xe2x80x94SO2NRdRe; wherein Rd is 4-heptyl-6-methyl-2-pyrimidyl, 5-methoxy-2-pyrimidyl, 2-pyridyl, phenyl, 2,6-dimethylphenyl, 2-thiazoyl, 2-trifluoromethylphenyl, or 3,5-dichlorophenyl; and Re is hydrogen or ethyl.
Another preferred group of compounds are compounds of the invention wherein R11 or R12 is xe2x80x94SO2NRdRe; wherein Rd and Re together with the atoms to which they are attached are piperidino or morpholino.
A specific group of compounds of the invention are compounds wherein R11 is hydrogen or alkyl; R12 is xe2x80x94SO2Rd; and R13 is hydrogen.
Another specific group of compounds of the invention are compounds wherein R11 is xe2x80x94SO2Rd; R12 is hydrogen or alkyl; and R13 is hydrogen.
When part of the group xe2x80x94SO2Rd, a specific value for Rd is alkyl, aryl, or heteroaryl.
When part of the group xe2x80x94SO2Rd, a specific value for Rd is aryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C1-6alkoxy, and xe2x80x94CF3.
When part of the group xe2x80x94SO2Rd, a specific value for Rd is phenyl optionally substituted with 1 or 2 substituents independently selected from halo and C1-6alkyl.
A preferred group of compounds of the invention are compounds wherein R11 or R12 is xe2x80x94SO2Rd; wherein Rd is phenyl, 4-chlorophenyl, methyl, or 4-fluorophenyl.
A specific group of compounds of the invention are compounds wherein at least one of R11, R12, and R13 is xe2x80x94ORd and each of the other two of R11, R12, and R13 is independently selected from the group consisting of hydrogen, alkyl, xe2x80x94O-alkyl, and halo; wherein any alkyl or xe2x80x94O-alkyl is optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo substituents.
A specific group of compounds of the invention are compounds wherein R11 is xe2x80x94ORd.
A specific group of compounds of the invention are compounds wherein R12 is xe2x80x94ORd.
A specific group of compounds of the invention are compounds wherein R13 is xe2x80x94ORd.
A specific group of compounds of the invention are compounds wherein R11 is hydrogen; R12 is xe2x80x94ORd; and R13 is hydrogen.
A specific group of compounds of the invention are compounds wherein R11 is xe2x80x94ORd; R12 is hydrogen; and R13 is hydrogen.
When part of the group xe2x80x94ORd, a specific value for Rd is alkyl, optionally substituted with one or more (e.g. 1, 2, 3, or 4) halo substituents and also optionally substituted with 1, 2, 3, or 4 aryl substituents, wherein each aryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, C1-6alkyl, C1-6alkoxy, hydroxy, amino, xe2x80x94NHC1-6alkyl, xe2x80x94N(C1-6alkyl)2, xe2x80x94OC(xe2x95x90O)C1-6alkyl, xe2x80x94C(xe2x95x90O)C1-6alkyl, xe2x80x94C(xe2x95x90O)OC1-6alkyl, xe2x80x94NHC(xe2x95x90O)C1-6alkyl, xe2x80x94C(xe2x95x90O)NHC1-6alkyl, carboxy, nitro, xe2x80x94CN, and xe2x80x94CF3.
When part of the group xe2x80x94ORd, a specific value for Rd is alkyl, optionally substituted with one or more (e.g. 1, 2, 3, or 4) halo substituents and also optionally substituted with 1 or 2 phenyl substituents, wherein each phenyl is optionally substituted with 1 or 2 substituents independently selected from halo, C1-6alkyl, C1-6alkoxy, hydroxy, xe2x80x94CN, and xe2x80x94CF3.
A specific group of compounds of the invention are compounds wherein R11 and R12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered ring comprising one or more carbon atoms and 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen; and R13 is selected from the group consisting of hydrogen, alkyl, xe2x80x94O-alkyl, and halo; wherein any alkyl or xe2x80x94O-alkyl is optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo substituents.
A more specific group of compounds of the invention are compounds wherein R11 and R13 together are xe2x80x94OCH2Oxe2x80x94, xe2x80x94OCH2CH2Oxe2x80x94, or xe2x80x94OCH2CH2CH2Oxe2x80x94.
A specific group of compounds of the invention are compounds wherein R11, R12, or R13 is methoxy, ethoxy, benzyloxy, or isopropoxy.
A specific group of compounds of the invention are compounds wherein R11, R12, and R13 are each hydrogen.
A specific group of compounds of the invention are compounds wherein at least one of R11, R12, and R13 is alkyl and each of the other two of R11, R12, and R13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, wherein any alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents; or wherein R11 and R12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered carbocyclic ring.
A specific group of compounds of the invention are compounds wherein at least one of R11, R12, and R13 is alkyl and each of the other two of R11, R12, and R13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, wherein any alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents.
A specific group of compounds of the invention are compounds wherein R11 and R12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered carbocyclic ring; and R3 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, hydroxy, and halo, wherein any alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents.
A specific value for R13 is hydrogen.
A specific group of compounds of the invention are compounds wherein R11 is hydrogen; R12 is alkyl; and R13 is hydrogen.
A specific group of compounds of the invention are compounds wherein R11 is alkyl; R12 is hydrogen; and R13 is hydrogen.
A preferred group of compounds of the invention are compounds wherein R11 or R12 is methyl, ethyl, isopropyl, or cyclohexyl; or wherein R11 and R12 taken together are xe2x80x94CH2CH2CH2xe2x80x94.
A specific group of compounds of the invention are compounds wherein at least one of R11, R12, and R3 is aryl; and each of the other two of R11, R12, and R13 is independently selected from the group consisting of hydrogen, alkyl, xe2x80x94O-alkyl, and halo, wherein any alkyl or xe2x80x94O-alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents;
or wherein R11 and R12 together with the atoms to which they are attached form a fused benzo ring, which benzo ring can optionally be substituted with 1, 2, 3, or 4 Rc; and R13 is independently selected from the group consisting of hydrogen, alkyl, xe2x80x94O-alkyl, and halo, wherein any alkyl or xe2x80x94O-alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents.
A specific group of compounds of the invention are compounds wherein at least one of R11, R13, and R13 is aryl; and each of the other two of R11, R12, and R13 is independently selected from the group consisting of hydrogen, alkyl, xe2x80x94O-alkyl, and halo, wherein any alkyl or xe2x80x94O-alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents.
A specific group of compounds of the invention are compounds wherein R11 is phenyl, optionally substituted with 1, 2, 3, or 4 alkyl, xe2x80x94ORd, xe2x80x94NO2, halo, xe2x80x94NRdRe, xe2x80x94C(xe2x95x90O)Rd, xe2x80x94CO2Rd, xe2x80x94OC(xe2x95x90O)Rd, xe2x80x94CN, xe2x80x94C(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)Re, xe2x80x94OC(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)ORe, xe2x80x94NRdC(xe2x95x90O)NRdRe, xe2x80x94CRd(xe2x95x90Nxe2x80x94ORe), xe2x80x94CF3, or xe2x80x94OCF3; R12 is selected from the group consisting of hydrogen and xe2x80x94O-alkyl, optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo; and R13 is hydrogen.
A specific group of compounds of the invention are compounds wherein R11 is phenyl, optionally substituted with 1, 2, 3, or 4 alkyl, xe2x80x94ORd, halo, xe2x80x94CF3, or xe2x80x94OCF3; R12 is selected from the group consisting of hydrogen and xe2x80x94O-alkyl, optionally substituted with aryl, or with one or more (e.g. 1, 2, 3, or 4) halo; and R13 is hydrogen.
A specific group of compounds of the invention are compounds wherein R11 or R12 is phenyl.
A specific group of compounds of the invention are compounds wherein R11 and R12 together with the atoms to which they are attached form a fused benzo ring.
A specific group of compounds of the invention are compounds wherein at least one of R11, R12, and R13 is heterocyclyl; and each of the other two of R11, R12, and R13 is independently selected from the group consisting of hydrogen, alkyl, xe2x80x94O-alkyl, and halo, wherein any alkyl or xe2x80x94O-alkyl is optionally substituted with aryl, with one or more (e.g. 1, 2, 3, or 4) halo, or with 1 or 2-O-alkyl substituents;
or wherein R11 and R12 together with the atoms to which they are attached form a heterocyclic ring.
A specific group of compounds of the invention are compounds wherein R11 and R12 together with the atoms to which they are attached form a saturated or unsaturated 5, 6, or 7 membered ring comprising carbon atoms and optionally comprising 1 or 2 heteroatoms independently selected from oxygen, sulfur or nitrogen, wherein said ring can optionally be substituted on carbon with one or two oxo (xe2x95x90O), and wherein said ring is fused to a benzo ring, which benzo ring can optionally be substituted with 1, 2, 3, or 4 Re; and R13 is independently selected from the group consisting of hydrogen, alkyl, xe2x80x94O-alkyl, and halo, wherein any alkyl or xe2x80x94O-alkyl is optionally substituted with aryl, with one or more halo, or with 1 or 2-O-alkyl substituents.
A specific group of compounds of the invention are compounds wherein R11 or R12 is 2,3-dihydro-5-methyl-3-oxo-1-pyrazolyl; or wherein R11 and R12 together with the atoms to which they are attached form a 2-oxobenzopyran ring.
Another specific group of compounds of the invention are compounds wherein R11 or R12 is anilino, trifluoromethoxy, or methoxycarbonyl.
A sub-group of compounds of the invention are compounds of formula (I) wherein each of R1-R5 is independently selected from the group consisting of hydrogen, alkyl, and Ra; wherein each Ra is independently xe2x80x94ORd, halo, xe2x80x94NRdRe, xe2x80x94NRdC(xe2x95x90O)Re, or xe2x80x94OC(xe2x95x90O)NRdRe;
or R1 and R2, or R4 and R5, are joined together to form a group selected from the group consisting of xe2x80x94C(Rd)xe2x95x90C(Rd)C(xe2x95x90O)NRdxe2x80x94, xe2x80x94CRdRdCRdRdxe2x80x94C(xe2x95x90O)NRdxe2x80x94, xe2x80x94NRdC(xe2x95x90O)C(Rd)xe2x95x90C(Rd)xe2x80x94, xe2x80x94NRdC(xe2x95x90O)CRdRdxe2x80x94CRdRdxe2x80x94, xe2x80x94NRdC(xe2x95x90O)Sxe2x80x94, and xe2x80x94SC(xe2x95x90O)NRdxe2x80x94;
R6, R8, and R10 are each hydrogen;
each of R11 and R12 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, xe2x80x94NO2, halo, xe2x80x94NRdRe, xe2x80x94CO2Rd, xe2x80x94OC(xe2x95x90O)Rd, xe2x80x94CN, xe2x80x94C(xe2x95x90O)NRdRe, xe2x80x94NRdC(xe2x95x90O)Re, xe2x80x94ORd, xe2x80x94S(O)mRd, xe2x80x94NRdxe2x80x94NRdxe2x80x94C(xe2x95x90O)Rd, xe2x80x94NRdxe2x80x94Nxe2x95x90CRdRd, xe2x80x94N(NRdRe)Rd, and xe2x80x94S(O)2NRdRe;
wherein for R1-R5, R11, and R12, each alkyl is optionally substituted with Rm, or with 1, 2, 3, or 4 substituents independently selected from R11; for R11 and R12, each aryl and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rc, and for R11 and R12, each cycloalkyl and heterocyclyl is optionally substituted with 1, 2, 3, or 4 substituents independently selected from Rb and Rc;
R13 is hydrogen;
the group comprising xe2x80x94NR10 is meta or para to the group comprising R7; and
w is 0, 1, or 2.
Preferably within the above sub-group of compounds, each of R11 and R12 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, xe2x80x94ORd, xe2x80x94S(O)mRd, and xe2x80x94S(O)2NRdRe; wherein each alkyl is optionally substituted with 1 or 2 substituents independently selected from Rb, each aryl is optionally substituted with 1 or 2 substituents independently selected from Rc, and each heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from Rb and Rc; and m is 0 or 2.
More preferably for such compounds, R7 is hydrogen;
each of R11 and R12 is independently selected from the group consisting of hydrogen, C1-6alkyl, cyclohexyl, phenyl, pyrazolinyl, xe2x80x94ORd, xe2x80x94S(O)mRd, and xe2x80x94S(O)2NRdRe;
w is 0; and
Rd and Re are independently selected from the group consisting of hydrogen, C1-6alkyl, phenyl, xe2x80x94CF3, and C1-3alkyl, pyridyl, thiazolyl, pyrimidinyl, and pyrazolinyl, where each phenyl is optionally substituted with 1 or 2 substitutents independently selected from halo, xe2x80x94CF3, and C1-3alkyl, each pyrimidinyl is optionally substituted with 1 or 2 substitutents independently selected from C1-3alkyl and OC1-3alkyl, and each pyrazolinyl is optionally substituted with 1 or 2 substitutents independently selected from C1-3alkyl and carboxy; or
Rd and Re, together with the nitrogen atom to which they are attached are morpholino or piperidino.
Within the more preferred sub-group, one most preferred sub-group of compounds are compounds wherein R11 is xe2x80x94SRd and R12 is hydrogen, or R11 is hydrogen and R12 is xe2x80x94SRd, wherein Rd is selected from the group consisting of C1-3alkyl, phenyl, and pyrimidinyl, and wherein each phenyl is optionally substituted with 1 or 2 substitutents independently selected from halo and C1-3alkyl, and each pyrimidinyl is optionally substituted with C1-3alkyl.
Another most preferred sub-group of compounds are compounds wherein R11 is xe2x80x94S(O)2NRdRe and R12 is hydrogen or alkyl, or R11 is hydrogen or alkyl and R12 is xe2x80x94S(O)2NRdRe, wherein Rd and Re are independently selected from the group consisting of hydrogen, C1-3alkyl, phenyl, pyridyl, thiazolyl, and pyrimidinyl, and wherein each phenyl is optionally substituted with 1 substitutent selected from halo and C1-3alkyl, and each pyrimidinyl is optionally substituted with 1 substitutent selected from C1-3alkyl and Oxe2x80x94C1-3alkyl; or Rd and Re, together with the nitrogen atom to which they are attached are morpholino or piperidino.
Another most preferred sub-group of compounds are compounds wherein R11 is xe2x80x94SO2Rd and R12 is hydrogen, or R11 is hydrogen and R12 is xe2x80x94SO2Rd, wherein R11 is C1-3alkyl or phenyl, and wherein each phenyl is optionally substituted with 1 substituent selected from halo and C1-3alkyl.
Another most preferred sub-group of compounds are compounds wherein R11 is xe2x80x94ORd and R12 is hydrogen or xe2x80x94ORd; or R11 is hydrogen and R12 is xe2x80x94ORd, wherein Rd is C1-3alkyl.
Another most preferred sub-group of compounds are compounds wherein R11 is C1-3alkyl and R12 is hydrogen or C1-3alkyl; or R11 is cyclohexane and R12 is hydroxy.
Another most preferred sub-group of compounds are compounds wherein R11 is hydrogen or phenyl; and R12 is xe2x80x94OC1-3alkyl; or wherein R11 is phenyl and R12 is hydrogen.
Yet another most preferred sub-group of compounds within the more preferred sub-group defined above are compounds wherein R12 is hydrogen and R11 is SO2NRdRe, wherein Rd and Re, together with the nitrogen atom to which they are attached, are morpholino or piperidino.
Another preferred group of compounds of formula (I) are compounds of formula (II): 
wherein:
R4 is xe2x80x94CH2OH or xe2x80x94NHCHO and R5 is hydrogen; or R4 and R5 taken together are xe2x80x94NHC(xe2x95x90O)CHxe2x95x90CHxe2x80x94;
R11 is phenyl or heteroaryl, wherein each phenyl is optionally substituted with 1 or 2 substituents selected from halo, xe2x80x94ORd, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO2Rd, xe2x80x94C(xe2x95x90O)R, xe2x80x94C(xe2x95x90O)NRdRe, and C1-3alkyl, wherein C1-3alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and each Rd and Re is independently hydrogen or C1-3alkyl; and wherein each heteroaryl is optionally substituted with 1 or 2 C1-3alkyl substituents; and
R12 is hydrogen or xe2x80x94OC1-6alkyl.
More preferably, for compounds of formula (II), R11 is phenyl, optionally substituted with 1 or 2 substituents selected from halo, xe2x80x94ORd, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO2Rd, xe2x80x94C(xe2x95x90O)Rd, and C1-3alkyl, wherein C1-3alkyl is optionally substituted with 1 or 2 substituents selected from carboxy, hydroxy, and amino, and Rd is hydrogen or C1-3alkyl; or R11 is pyridyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl, or indolyl, each of which is optionally substituted with 1 or 2 C1-3alkyl substituents.
Most preferable are compounds of formula (II), wherein R11 is phenyl, pyridyl, or thiophenyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, xe2x80x94OCH3, xe2x80x94CN, and xe2x80x94CH2NH2; and R12 is hydrogen, xe2x80x94OCH3, or xe2x80x94OC2H5. Among most preferred compounds, particularly preferred are compounds of formula (H) wherein R4 and R5 taken together are xe2x80x94NHC(xe2x95x90O)CHxe2x95x90CHxe2x80x94, R11 is phenyl or pyridyl, wherein each phenyl is optionally substituted with 1 substituent selected from the group consisting of chloro, xe2x80x94OCH3, xe2x80x94CN, and xe2x80x94CH2NH2, and R12 is xe2x80x94OCH3.
A preferred compound is any one of compounds 1-102 shown in the Examples below.
Most preferred compounds of the invention include the following:
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(4-ethoxyphenyl)aminophenyl ]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine; and
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-hydroxymethyl-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine;
N-{2-[4-(4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-phenylphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-phenyl-4-ethoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(2-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(2-methoxyphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(3-cyanophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(4-aminomethylphenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(3-chlorophenyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamnine;
N-{2-[4-(3-(4-aminomethylphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(3-cyanophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(4-hydroxyphenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(3-pyridyl)phenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(3-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(4-pyridyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine;
N-{2-[4-(3-(thiophen-3-yl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine; and
N-{2-[4-(3-(3-chlorophenyl)-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamine.
The compounds of the invention contain one or more chiral centers. Accordingly, the invention includes racemic mixtures, pure stereoisomers (i.e. individual enantiomers or diastereomers), and stereoisomer-enriched mixtures of such isomers, unless otherwise indicated. When a particular stereoisomer is shown, it will be understood by those skilled in the art, that minor amounts of other stereoisomers may be present in the compositions of this invention unless otherwise indicated, provided that the utility of the composition as a whole is not eliminated by the presence of such other isomers. In particular, compounds of the invention contain a chiral center at the alkylene carbon in formulas (I) and (II) to which the hydroxy group is attached. When a mixture of stereoisomers is employed, it is advantageous for the amount of the stereoisomer with the (R) orientation at the chiral center bearing the hydroxy group to be greater than the amount of the corresponding (S) stereoisomer. When comparing stereoisomers of the same compound, the (R) stereoisomer is preferred over the (S) stereoisomer.
The compounds of the invention can be prepared using the methods and procedures described herein, or using similar methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be used to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. Representative examples of amino-protecting groups and hydroxy-protecting groups are given above. Typical procedures for their removal include the following. An acyl amino-protecting group or hydroxy-protecting group may conveniently be removed, for example, by treatment with an acid, such as trifluoroacetic acid. An arylmethyl group may conveniently be removed by hydrogenolysis over a suitable metal catalyst such as palladium on carbon. A silyl hydroxy-protecting group may conveniently be removed by treatment with a fluoride ion source, such as tetrabutylammonium fluoride, or by treatment with an acid, such as hydrochloric acid.
In addition, numerous protecting groups (including amino-protecting groups and hydroxy-protecting groups), and their introduction and removal, are described in Greene and Wuts, Protecting Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons, NY, 1991, and in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973.
Processes for preparing compounds of the invention are provided as further embodiments of the invention and are illustrated by the procedures below.
A compound of formula (I) can be prepared by deprotecting a corresponding compound of formula (III): 
wherein R15 is an amino-protecting group. Accordingly, the invention provides a method for preparing a compound of formula (I), comprising deprotecting a corresponding compound of formula (III), wherein R15 is an amino-protecting group (e.g. 1,1-(4-methoxyphenyl)methyl or benzyl).
A compound of formula (I) wherein R3 is hydroxy can be prepared by deprotecting a corresponding compound of formula (I) wherein R3 is xe2x80x94OPg1 and Pg1 is a hydroxy-protecting group. Accordingly, the invention provides a method for preparing a compound of formula (I) wherein R3 is hydroxy, comprising deprotecting a corresponding compound of formula (I) wherein R3 is xe2x80x94OPg1 and Pg1 is a hydroxy-protecting group (e.g. benzyl).
A compound of formula (I) wherein R3 is hydroxy can also be prepared by deprotecting a corresponding compound of formula (III) wherein R15 is an amino-protecting group and wherein R3 is xe2x80x94OPg1 wherein Pg1 is a hydroxy-protecting group. Accordingly, the invention provides a method for preparing a compound of formula (I), comprising deprotecting a corresponding compound of formula (III) wherein R15 is an amino-protecting group (e.g. benzyl) and R3 is xe2x80x94OPg1 wherein Pg1 is a hydroxy-protecting group (e.g. benzyl).
The invention also provides an intermediate compound of formula (III) wherein R15 is an amino-protecting group (e.g. 1,1-di-(4xe2x80x2-methoxyphenyl)methyl or benzyl); as well as an intermediate compound of formula (I) wherein R3 is xe2x80x94OPg1 and Pg1 is a hydroxy-protecting group; and an intermediate compound of formula (III) wherein R15 is an amino-protecting group (e.g. benzyl), R3 is xe2x80x94OPg1, and Pg1 is a hydroxy-protecting group (e.g. benzyl).
An intermediate compound of formula (III) can be prepared by reacting an amine of formula (V) with a compound of formula (IV), wherein R16 is hydrogen or a hydroxy-protecting group (e.g. tert-butyldimethylsilyl) and X is a suitable leaving group (e.g. bromo). 
Accordingly, the invention provides a method for preparing a compound of formula (III), comprising reacting a corresponding aniline of formula (V) with a corresponding compound of formula (IV), wherein X is a suitable leaving group (e.g. bromo) and R15 is an amino-protecting group, in the presence of a transition metal catalyst. When R16 is a hydroxy-protecting group, the intermediate formed by the reaction of a compound of formula (V) with a compound of formula (IV) is subsequently deprotected to form the intermediate of formula (III). Suitable conditions for this reaction as well as suitable leaving groups are illustrated in the Examples and are also known in the art.
A compound of formula (III) can also be prepared by reacting an amine of formula (VII): 
wherein R14 is hydrogen and R15 is an amino-protecting group (e.g. benzyl), with a compound of formula (VI), (VII), or (IX): 
wherein R16 is hydrogen or a hydroxy-protecting group (e.g. tert-butyldimethylsilyl) and Z is a leaving group.
Accordingly, the invention provides a method for preparing a compound of formula (III), comprising reacting a corresponding amine of formula (VII), wherein R14 is hydrogen and R15 is an amino-protecting group, with a corresponding compound of formula (VI), (VII), or (IX), wherein R16 is hydrogen or a hydroxy-protecting group and Z is a suitable leaving group (e.g. bromo). When R16 is a hydroxy-protecting group, the intermediate formed by the reaction of a compound of formula (VII) with a compound of formula (VI) is subsequently deprotected to form the intermediate of formula (III).
The invention also provides a method for preparing a compound of formula (I), wherein R3 is xe2x80x94OPg1 and Pg1 is a hydroxy-protecting group, comprising reacting a corresponding compound of formula (VII) wherein R14 and R15 are each hydrogen with a corresponding compound of formula (VI), wherein R3 is xe2x80x94OPg1 and Pg1 is a hydroxy-protecting group and R16 is a hydroxy-protecting group.
Depending on the specific values of the substituents, variations on the synthetic schemes described above can be employed, particularly in the order of coupling and deprotection reactions, to produce a compound of the invention. For example, a compound of formula (I) wherein R3 is hydroxy and R12 and R13 are hydrogen can be prepared by reacting an intermediate of formula (I) wherein R3 is xe2x80x94OPg1, where Pg1 is a hydroxy-protecting group, and R11 is a suitable leaving group (e.g. bromo) with an appropriately substituted boronic acid to form an intermediate, which is subsequently deprotected, as illustrated in Examples 65-102.
Additionally, a useful intermediate for preparing a compound of formula (VII), wherein R14 is hydrogen and R15 is an amino-protecting group, is a corresponding compound of formula (VII) wherein R14 is an amino-protecting group that can be removed in the presence of R15. A compound of formula (VII) wherein R14 is hydrogen and R15 is an amino-protecting group is itself also a useful intermediate for the preparation of a compound of formula (VII) where both R14 and R15 are hydrogen. Thus, the invention also provides novel intermediates of formula (VII), wherein R14 is hydrogen or an amino-protecting group, R15 is hydrogen or an amino-protecting group, and wherein R7-R13 and w have any of the values defined herein, or a salt thereof.
A preferred compound of formula (VII) is a compound wherein R14 and R15 are both hydrogen. Another preferred compound of formula (VII) is a compound wherein R14 is an alkoxycarbonyl protecting group (e.g. tert-butoxy carbonyl), and R15 is an arylmethyl protecting group (e.g. benzyl). Another preferred compound of formula (VII) is a compound wherein R14 is hydrogen, and R15 is an alkoxycarbonyl protecting group (e.g. tert-butoxy carbonyl).
The invention also provides pharmaceutical compositions comprising a compound of the invention. Accordingly, the compound, preferably in the form of a pharmaceutically-acceptable salt, can be formulated for any suitable form of administration, such as oral or parenteral administration, or administration by inhalation.
By way of illustration, the compound can be admixed with conventional pharmaceutical carriers and excipients and used in the form of powders, tablets, capsules, elixirs, suspensions, syrups, wafers, and the like. Such pharmaceutical compositions will contain from about 0.05 to about 90% by weight of the active compound, and more generally from about 0.1 to about 30%. The pharmaceutical compositions may contain common carriers and excipients, such as cornstarch or gelatin, lactose, magnesium sulfate, magnesium stearate, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid. Disintegrators commonly used in the formulations of this invention include croscarmellose, microcrystalline cellulose, cornstarch, sodium starch glycolate and alginic acid.
A liquid composition will generally consist of a suspension or solution of the compound or pharmaceutically-acceptable salt in a suitable liquid carrier(s), for example ethanol, glycerine, sorbitol, non-aqueous solvent such as polyethylene glycol, oils or water, optionally with a suspending agent, a solubilizing agent (such as a cyclodextrin), preservative, surfactant, wetting agent, flavoring or coloring agent. Alternatively, a liquid formulation can be prepared from a reconstitutable powder.
For example a powder containing active compound, suspending agent, sucrose and a sweetener can be reconstituted with water to form a suspension; a syrup can be prepared from a powder containing active ingredient, sucrose and a sweetener.
A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid compositions. Examples of such carriers include magnesium stearate, starch, lactose, sucrose, microcrystalline cellulose and binders, for example polyvinylpyrrolidone. The tablet can also be provided with a color film coating, or color included as part of the carrier(s). In addition, active compound can be formulated in a controlled release dosage form as a tablet comprising a hydrophilic or hydrophobic matrix.
A composition in the form of a capsule can be prepared using routine encapsulation procedures, for example by incorporation of active compound and excipients into a hard gelatin capsule. Alternatively, a semi-solid matrix of active compound and high molecular weight polyethylene glycol can be prepared and filled into a hard gelatin capsule; or a solution of active compound in polyethylene glycol or a suspension in edible oil, for example liquid paraffin or fractionated coconut oil can be prepared and filled into a soft gelatin capsule.
Tablet binders that can be included are acacia, methylcellulose, sodium carboxymethylcellulose, poly-vinylpyrrolidone (Povidone), hydroxypropyl methylcellulose, sucrose, starch and ethylcellulose. Lubricants that can be used include magnesium stearate or other metallic stearates, stearic acid, silicone fluid, talc, waxes, oils and colloidal silica.
Flavoring agents such as peppermint, oil of wintergreen, cherry flavoring or the like can also be used. Additionally, it may be desirable to add a coloring agent to make the dosage form more attractive in appearance or to help identify the product.
The compounds of the invention and their pharmaceutically-acceptable salts that are active when given parenterally can be formulated for intramuscular, intrathecal, or intravenous administration.
A typical composition for intra-muscular or intrathecal administration will consist of a suspension or solution of active ingredient in an oil, for example arachis oil or sesame oil. A typical composition for intravenous or intrathecal administration will consist of a sterile isotonic aqueous solution containing, for example active ingredient and dextrose or sodium chloride, or a mixture of dextrose and sodium chloride. Other examples are lactated Ringer""s injection, lactated Ringer""s plus dextrose injection, Normosol-M and dextrose, Isolyte E, acylated Ringer""s injection, and the like. Optionally, a co-solvent, for example, polyethylene glycol; a chelating agent, for example, ethylenediamine tetracetic acid; a solubilizing agent, for example, a cyclodextrin; and an anti-oxidant, for example, sodium metabisulphite, may be included in the formulation. Alternatively, the solution can be freeze dried and then reconstituted with a suitable solvent just prior to administration.
The compounds of this invention and their pharmaceutically-acceptable salts which are active on topical administration can be formulated as transdermal compositions or transdermal delivery devices (xe2x80x9cpatchesxe2x80x9d). Such compositions include, for example, a backing, active compound reservoir, a control membrane, liner and contact adhesive. Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, for example, U.S. Pat. No. 5,023,252. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
One preferred manner for administering a compound of the invention is inhalation. Inhalation is an effective means for delivering an agent directly to the respiratory tract. There are three general types of pharmaceutical inhalation devices: nebulizer inhalers, dry powder inhalers (DPI), and metered-dose inhalers (MDI). Nebulizer devices produce a stream of high velocity air that causes a therapeutic agent to spray as a mist which is carried into the patient""s respiratory tract. The therapeutic agent is formulated in a liquid form such as a solution or a suspension of micronized particles of respirable size, where micronized is typically defined as having about 90% or more of the particles with a diameter of less than about 10 xcexcm. A typical formulation for use in a conventional nebulizer device is an isotonic aqueous solution of a pharmaceutical salt of the active agent at a concentration of the active agent of between about 0.05 xcexcg/mL and about 10 mg/mL.
DPI""s typically administer a therapeutic agent in the form of a free flowing powder that can be dispersed in a patient""s air-stream during inspiration. In order to achieve a free flowing powder, the therapeutic agent can be formulated with a suitable excipient, such as lactose or starch. A dry powder formulation can be made, for example, by combining dry lactose having a particle size between about 1 xcexcm and about 100 xcexcm with micronized particles of a pharmaceutical salt of the active agent and dry blending. Alternative, the agent can be formulated without excipients. The formulation is loaded into a dry powder dispenser, or into inhalation cartridges or capsules for use with a dry powder delivery device.
Examples of DPI delivery devices provided commercially include Diskhaler (GlaxoSmithKline, Research Triangle Park, N.C.) (see, e.g., U.S. Pat. No. 5,035,237); Diskus (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 6,378,519; Turbuhaler (AstraZeneca, Wilmington, Del.) (see, e.g., U.S. Pat. No. 4,524,769); and Rotahaler (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 4,353,365). Further examples of suitable DPI devices are described in U.S. Pat. Nos. 5,415,162, 5,239,993, and 5,715,810 and references therein.
MDI""s typically discharge a measured amount of therapeutic agent using compressed propellant gas. Formulations for MDI administration include a solution or suspension of active ingredient in a liquefied propellant. While chlorofluorocarbons, such as CCl3F, conventionally have been used as propellants, due to concerns regarding adverse affects of such agents on the ozone layer, formulations using hydrofluoroalklanes (HFA), such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3,-heptafluoro-n-propane, (HFA 227) have been developed. Additional components of HFA formulations for MDI administration include co-solvents, such as ethanol or pentane, and surfactants, such as sorbitan trioleate, oleic acid, lecithin, and glycerin. (See, for example, U.S. Pat. No. 5,225,183, EP 0717987 A2, and WO 92/22286.)
Thus, a suitable formulation for MDI administration can include from about 0.01% to about 5% by weight of a pharmaceutical salt of active ingredient, from about 0% to about 20% by weight ethanol, and from about 0% to about 5% by weight surfactant, with the remainder being the HFA propellant. In one approach, to prepare the formulation, chilled or pressurized hydrofluoroalkane is added to a vial containing the pharmaceutical salt of active compound, ethanol (if present) and the surfactant (if present). To prepare a suspension, the pharmaceutical salt is provided as micronized particles. The formulation is loaded into an aerosol canister, which forms a portion of an MDI device. Examples of MDI devices developed specifically for use with HFA propellants are provided in U.S. Pat. Nos. 6,006,745 and 6,143,277.
In an alternative preparation, a suspension formulation is prepared by spray drying a coating of surfactant on micronized particles of a pharmaceutical salt of active compound. (See, for example, WO 99/53901 and WO 00/61108.) For additional examples of processes of preparing respirable particles, and formulations and devices suitable for inhalation dosing see U.S. Pat. Nos. 6,268,533, 5,983,956, 5,874,063, and 6,221,398, and WO 99/55319 and WO 00/30614.
It will be understood that any form of the compounds of the invention, (i.e. free base, pharmaceutical salt, or solvate) that is suitable for the particular mode of administration, can be used in the pharmaceutical compositions discussed above.
The active compound is effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
Suitable doses of the therapeutic agent for inhalation administration are in the general range of from about 0.05 xcexcg/day to about 1000 xcexcg/day, preferably from about 0.5 xcexcg/day to about 500 xcexcg/day. A compound can be administered in a periodic dose: weekly, multiple times per week, daily, or multiple doses per day. The treatment regimen may require administration over extended periods of time, for example, for several weeks or months, or the treatment regimen may require chronic administration. Suitable doses for oral administration are in the general range of from about 0.05 xcexcg/day to about 100 mg/day, preferably 0.5 to 1000 xcexcg/day.
The present active agents can also be co-administered with one or more other therapeutic agents. For example, for the treatment of asthma or of chronic obstructive pulmonary disease, the present agents can be administered in combination with a muscarinic receptor antagonist (e.g. ipatropium bromide or tiotropium) or a steroidal anti-inflammatory agent (e.g. fluticasone propionate, beclomethasone, budesonide, mometasone, ciclesonide, or triamcinolone). In addition, the present active agents can be co-administered with an agent having anti-inflammatory and/or bronchodilating or other beneficial activity, including but not limited to, a phosphodiesterase (PDE) inhibitor (e.g. theophylline); a PDE4 inhibitor (e.g. cilomilast or roflumilast); an immunoglobulin antibody (xcex1IgE antibody); a leukotriene antagonist (e.g. monteleukast); a cytokine antagonist therapy, such as, an interleukin antibody (xcex1IL antibody), specifically, an xcex1IL-4 therapy, an xcex1IL-13 therapy, or a combination thereof; a protease inhibitor, such as an elastase or tryptase inhibitor; cromolyn sodium; nedocromil sodium; and sodium cromoglycate. Further, the present agents can be co-administered with an antiinfective agent or antihistamines. Suitable doses for the other therapeutic agents administered in combination with a compound of the invention are in the range of about 0.05 xcexcg/day to about 100 mg/day.
Accordingly, the compositions of the invention can optionally comprise a compound of the invention as well as another therapeutic agent as described above.
Additional suitable carriers for formulations of the active compounds of the present invention can be found in Remington: The Science and Practice of Pharmacy, 20th Edition, Lippincott Williams and Wilkins, Philadelphia, Pa., 2000. The following non-limiting examples illustrate representative pharmaceutical compositions of the invention.
This example illustrates the preparation of a representative pharmaceutical composition for oral administration of a compound of this invention:
The above ingredients are mixed and introduced into a hard-shell gelatin capsule.
This example illustrates the preparation of another representative pharmaceutical composition for oral administration of a compound of this invention:
The above ingredients are mixed intimately and pressed into single scored tablets.
This example illustrates the preparation of a representative pharmaceutical composition for oral administration of a compound of this invention.
An oral suspension is prepared having the following composition.
This example illustrates the preparation of a representative pharmaceutical composition containing a compound of this invention.
An injectable preparation buffered to a pH of 4 is prepared having the following composition:
This example illustrates the preparation of a representative pharmaceutical composition for injection of a compound of this invention.
A reconstituted solution is prepared by adding 20 mL of sterile water to 1 g of the compound of this invention. Before use, the solution is then diluted with 200 mL of an intravenous fluid that is compatible with the active compound. Such fluids are chosen from 5% dextrose solution, 0.9% sodium chloride, or a mixture of 5% dextrose and 0.9% sodium chloride. Other examples are lactated Ringer""s injection, lactated Ringer""s plus 5% dextrose injection, Normosol-M and 5% dextrose, Isolyte E, and acylated Ringer""s injection.
This example illustrates the preparation of a representative pharmaceutical composition containing a compound of this invention.
An injectable preparation is prepared having the following composition:
The above ingredients are blended and the pH is adjusted to 3.5xc2x10.5 using 0.5 N HCl or 0.5 N NaOH.
This example illustrates the preparation of a representative pharmaceutical composition for topical application of a compound of this invention.
All of the above ingredients, except water, are combined and heated to 60xc2x0 C. with stirring. A sufficient quantity of water at 60xc2x0 C. is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. 100 g.
This example illustrates the preparation of a representative pharmaceutical composition containing a compound of the invention.
An aqueous aerosol formulation for use in a nebulizer is prepared by dissolving 0.1 mg of a pharmaceutical salt of active compound in a 0.9% sodium chloride solution acidified with citric acid. The mixture is stirred and sonicated until the active salt is dissolved. The pH of the solution is adjusted to a value in the range of from 3 to 8 by the slow addition of NaOH.
This example illustrates the preparation of a dry powder formulation containing a compound of the invention for use in inhalation cartridges.
Gelatin inhalation cartridges are filled with a pharmaceutical composition having the following ingredients:
The pharmaceutical salt of active compound is micronized prior to blending with lactose. The contents of the cartridges are administered using a powder inhaler.
This example illustrates the preparation of a dry powder formulation containing a compound of the invention for use in a dry powder inhalation device.
A pharmaceutical composition is prepared having a bulk formulation ratio of micronized pharmaceutical salt to lactose of 1:200. The composition is packed into a dry powder inhalation device capable of delivering between about 10 xcexcg and about 100 xcexcg of active drug ingredient per dose.
This example illustrates the preparation of a formulation containing a compound of the invention for use in a metered dose inhaler.
A suspension containing 5% pharmaceutical salt of active compound, 0.5% lecithin, and 0.5% trehalose is prepared by dispersing 5 g of active compound as micronized particles with mean size less than 10 xcexcm in a colloidal solution formed from 0.5 g of trehalose and 0.5 g of lecithin dissolved in 100 mL of demineralized water. The suspension is spray dried and the resulting material is micronized to particles having a mean diameter less than 1.5 xcexcm. The particles are loaded into canisters with pressurized 1,1,1,2-tetrafluoroethane.
This example illustrates the preparation of a formulation containing a compound of the invention for use in a metered dose inhaler.
A suspension containing 5% pharmaceutical salt of active compound and 0.1% lecithin is prepared by dispersing 10 g of active compound as micronized particles with mean size less than 10 xcexcm in a solution formed from 0.2 g of lecithin dissolved in 200 mL of demineralized water. The suspension is spray dried and the resulting material is micronized to particles having a mean diameter less than 1.5 xcexcm. The particles are loaded into canisters with pressurized 1,1,1,2,3,3,3-heptafluoro-n-propane.
The compounds of this invention, and their pharmaceutically-acceptable salts, exhibit biological activity and are useful for medical treatment. The ability of a compound to bind to the xcex22 adrenergic receptor, as well as its selectivity, agonist potency, and intrinsic activity can be demonstrated using in vitro Tests A-C below, in vivo Test D, below, or can be demonstrated using other tests that are known in the art.
HEK-293 derived cell lines stably expressing cloned human xcex21 or xcex22 adrenergic receptors, respectively, were grown to near confluency in DMEM with 10% dialyzed FBS in the presence of 500 xcexcg/mL Geneticin. The cell monolayer was lifted with Versene 1:5,000 (0.2 g/L EDTA in PBS) using a cell scraper. Cells were pelleted by centrifugation at 1,000 rpm, and cell pellets were either stored frozen at xe2x88x9280xc2x0 C. or membranes were prepared immediately. For preparation, cell pellets were resuspended in lysis buffer (10 mM Tris/HCL pH 7.4@4xc2x0 C., one tablet of xe2x80x9cComplete Protease Inhibitor Cocktail Tablets with 2 mM EDTAxe2x80x9d per 50 mL buffer (Roche cat. #1697498, Roche Molecular Biochemicals, Indianapolis, Ind.)) and homogenized using a tight-fitting Dounce glass homogenizer (20 strokes) on ice. The homogenate was centrifuged at 20,000xc3x97g, the pellet was washed once with lysis buffer by resuspension and centrifugation as above. The final pellet was resuspended in membrane buffer (75 mM Tris/HCl pH 7.4, 12.5mM MgCl2, 1 mM EDTA@25xc2x0 C.). Protein concentration of the membrane suspension was determined by the method of Bradford (Bradford M M., Analytical Biochemistry, 1976, 72, 248-54). Membranes were stored frozen in aliquots at xe2x88x9280xc2x0 C.
Binding assays were performed in 96-well microtiter plates in a total assay volume of 100 xcexcL with 5 xcexcg membrane protein for membranes containing the human xcex22 adrenergic receptor, or 2.5 xcexcg membrane protein for membranes containing the human xcex21 adrenergic receptor in assay buffer (75 mM Tris/HCl pH 7.4@25xc2x0 C., 12.5 mM MgCl2, 1 mM EDTA, 0.2% BSA). Saturation binding studies for determination of Kd values of the radioligand were done using [3H]dihydroalprenolol (NET-720, 100 Ci/mmol, PerkinElmer Life Sciences Inc., Boston, Mass.) at 10 different concentrations ranging from 0.01 nM-200 nM. Displacement assays for determination of pKi values of compounds were done with [3H]dihydroalprenolol at 1 nM and 10 different concentrations of compound ranging from 40 xcexcM-10 xcexcM. Compounds were dissolved to a concentration of 10 mM in dissolving buffer (25 mM Gly-HCl pH 3.0 with 50% DMSO), then diluted to 1 mM in 50 mM Gly-HCl pH 3.0, and from there serially diluted into assay buffer. Non-specific binding was determined in the presence of 10 xcexcM unlabeled alprenolol. Assays were incubated for 90 minutes at room temperature, binding reactions were terminated by rapid filtration over GF/B glass fiber filter plates (Packard BioScience Co., Meriden, Conn.) presoaked in 0.3% polyethyleneimine. Filter plates were washed three times with filtration buffer (75 mM Tris/HCl pH 7.4@4xc2x0 C., 12.5 mM MgCl2, 1 mM EDTA) to remove unbound radioactivity. Plates were dried, 50 xcexcL Microscint-20 liquid scintillation fluid (Packard BioScience Co., Meriden, Conn.) was added and plates were counted in a Packard Topcount liquid scintillation counter (Packard BioScience Co., Meriden, Conn.). Binding data were analyzed by nonlinear regression analysis with the GraphPad Prism Software package (GraphPad Software, Inc., San Diego, Calif.) using the 3-parameter model for one-site competition. The curve minimum was fixed to the value for nonspecific binding, as determined in the presence of 10 xcexcM alprenolol. Ki values for compounds were calculated from observed IC50 values and the Kd value of the radioligand using the Cheng-Prusoff equation (Cheng Y, and Prusoff W H., Biochemical Pharmacology, 1973, 22, 23, 3099-108). The receptor subtype selectivity was calculated as the ratio of Ki(xcex21)/Ki(xcex22). All of the compounds tested demonstrated greater binding at the xcex22 adrenergic receptor than at the xcex21 adrenergic receptor, i.e. Ki(xcex21) greater than Ki(xcex22). Most preferred compounds of the invention demonstrated a selectivity greater than about 20.
For the determination of agonist potencies, a HEK-293 cell line stably expressing cloned human xcex22 adrenergic receptor (clone H24.14) was grown to confluency in medium consisting of DMEM supplemented with 10% FBS and 500 xcexcg/mL Geneticin. The day before the assay, antibiotics were removed from the growth-medium.
cAMP assays were performed in a radioimmunoassay format using the Flashplate Adenylyl Cyclase Activation Assay System with 125I-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, Mass.), according to the manufacturers instructions.
On the day of the assay, cells were rinsed once with PBS, lifted with Versene 1:5,000 (0.2 g/L EDTA in PBS) and counted. Cells were pelleted by centrifugation at 1,000 rpm and resuspended in stimulation buffer prewarmed to 37xc2x0 C. at a final concentration of 800,000 cells/mL. Cells were used at a final concentration of 40,000 cells/well in the assay. Compounds were dissolved to a concentration of 10 mM in dissolving buffer (25 mM Gly-HCl pH 3.0 with 50% DMSO), then diluted to 1 mM in 50 mM Gly-HCl pH 3.0, and from there serially diluted into assay buffer (75 mM Tris/HCl pH 7.4@25xc2x0 C., 12.5 mM MgCl2, 1 mM EDTA, 0.2% BSA). Compounds were tested in the assay at 10 different concentrations, ranging from 2.5 xcexcM to 9.5 pM. Reactions were incubated for 10 min at 37xc2x0 C. and stopped by addition of 100 xcexcl ice-cold detection buffer. Plates were sealed, incubated over night at 4xc2x0 C. and counted the next morning in a topcount scintillation counter (Packard BioScience Co., Meriden, Conn.). The amount of cAMP produced per mL of reaction was calculated based on the counts observed for the samples and cAMP standards, as described in the manufacturer""s user manual. Data were analyzed by nonlinear regression analysis with the GraphPad Prism Software package (GraphPad Software, Inc., San Diego, Calif.) using the 4-parameter model for sigmoidal dose-response with variable slope. Agonist potencies were expressed as pEC50 values. All of the compounds tested demonstrated activity at the xcex22 adrenergic receptor in this assay, as evidenced by pEC50 values greater than about 5. Most preferred compounds of the invention demonstrated pEC50 values greater than about 7.
For the determination of agonist potencies and efficacies (intrinsic activities) in a cell line expressing endogenous levels of xcex22 adrenergic receptor, a human lung epithelial cell line (BEAS-2B) was used (ATCC CRL-9609, American Type Culture Collection, Manassas, Va.) (January B, et al., British Journal of Pharmacology, 1998, 123, 4, 701-11). Cells were grown to 75-90% confluency in complete, serum-free medium (LHC-9 MEDIUM containing Epinephrine and Retinoic Acid, cat #181-500, Biosource International, Camarillo, Calif.). The day before the assay, medium was switched to LHC-8 (No epinephrine or retinoic acid, cat #141-500, Biosource International, Camarillo, Calif.).
cAMP assays were performed in a radioimmunoassay format using the Flashplate Adenylyl Cyclase Activation Assay System with 125I-cAMP (NEN SMP004, PerkinElmer Life Sciences Inc., Boston, Mass.), according to the manufacturers instructions.
On the day of the assay, cells were rinsed with PBS, lifted by scraping with 5 mM EDTA in PBS, and counted. Cells were pelleted by centrifugation at 1,000 rpm and resuspended in stimulation buffer prewarmed to 37xc2x0 C. at a final concentration of 600,000 cells/mL. Cells were used at a final concentration of 30,000 cells/well in the assay. Compounds were dissolved to a concentration of 10 mM in dissolving buffer (25 mM Gly-HCl pH 3.0 with 50% DMSO), then diluted to 1 mM in 50 mM Gly-HCl pH 3.0, and from there serially diluted into assay buffer (75 mM Tris/HCl pH 7.4@25xc2x0 C., 12.5 mM MgCl2, 1 mM EDTA, 0.2% BSA).
Compounds were tested in the assay at 10 different concentrations, ranging from 10 xcexcM to 40 pM. Maximal response was determined in the presence of 10 xcexcM Isoproterenol. Reactions were incubated for 10 min at 37xc2x0 C. and stopped by addition of 100 xcexcl ice-cold detection buffer. Plates were sealed, incubated over night at 4xc2x0 C. and counted the next morning in a topcount scintillation counter (Packard BioScience Co., Meriden, Conn.). The amount of cAMP produced per mL of reaction was calculated based on the counts observed for samples and cAMP standards, as described in the manufacturer""s user manual. Data were analyzed by nonlinear regression analysis with the GraphPad Prism Software package (GraphPad Software, Inc., San Diego, Calif.) using the 4-parameter model for sigmoidal dose-response with variable slope. Compounds of the invention tested in this assay demonstrated pEC50 values greater than about 7.
Compound efficacy (%Eff) was calculated from the ratio of the observed Emax (TOP of the fitted curve) and the maximal response obtained for 10 xcexcM isoproterenol and was expressed as %Eff relative to isoproterenol. The compounds tested demonstrated a %Eff greater than about 20.
Groups of 6 male guinea pigs (Duncan-Hartley (HsdPoc:DH) Harlan, Madison, Wis.) weighing between 250 and 350 g were individually identified by cage cards. Throughout the study animals were allowed access to food and water ad libitum.
Test compounds were administered via inhalation over 10 minutes in a whole-body exposure dosing chamber (RandS Molds, San Carlos, Calif.). The dosing chambers were arranged so that an aerosol was simultaneously delivered to 6 individual chambers from a central manifold. Following a 60 minute acclimation period and a 10 minute exposure to nebulized water for injection (WFI), guinea pigs were exposed to an aerosol of test compound or vehicle (WFI). These aerosols were generated from aqueous solutions using an LC Star Nebulizer Set (Model 22F51, PARI Respiratory Equipment, Inc. Midlothian, Va.) driven by a mixture of gases (CO2=5%, O2=21% and N2=74%) at a pressure of 22 psi. The gas flow through the nebulizer at this operating pressure was approximately 3 L/minute. The generated aerosols were driven into the chambers by positive pressure. No dilution air was used during the delivery of aerosolized solutions. During the 10 minute nebulization, approximately 1.8 mL of solution was nebulized. This was measured gravimetrically by comparing pre-and post-nebulization weights of the filled nebulizer.
The bronchoprotective effects of compounds administered via inhalation were evaluated using whole body plethysmography at 1.5, 24, 48 and 72 hours post-dose. Forty-five minutes prior to the start of the pulmonary evaluation, each guinea pig was anesthetized with an intramuscular injection of ketamine (43.75 mg/kg), xylazine (3.50 mg/kg) and acepromazine (1.05 mg/kg). After the surgical site was shaved and cleaned with 70% alcohol, a 2-5 cm midline incision of the ventral aspect of the neck was made. Then, the jugular vein was isolated and cannulated with a saline-filled polyethylene catheter (PE-50, Becton Dickinson, Sparks, Md.) to allow for intravenous infusions of a 0.1 mg/mL solution of acetylcholine (Ach), (Sigma-Aldrich, St. Louis, Mo.) in saline. The trachea was then dissected free and cannulated with a 14G teflon tube (#NE-014, Small Parts, Miami Lakes, Fla.). If required, anesthesia was maintained by additional intramuscular injections of the aforementioned anesthetic cocktail. The depth of anesthesia was monitored and adjusted if the animal responded to pinching of its paw or if the respiration rate was greater than 100 breaths/minute.
Once the cannulations were complete, the animal was placed into a plethysmograph (#PLY3114, Buxco Electronics, Inc., Sharon, Conn.) and an esophageal pressure cannula was inserted to measure pulmonary driving pressure (pressure). The teflon tracheal tube was attached to the opening of the plethysmograph to allow the guinea pig to breathe room air from outside the chamber. The chamber was then sealed. A heating lamp was used to maintain body temperature and the guinea pig""s lungs were inflated 3 times with 4 mL of air using a 10 mL calibration syringe (#5520 Series, Hans Rudolph, Kansas City, Mo.) to ensure that the lower airways had not collapsed and that the animal did not suffer from hyperventilation.
Once it was determined that baseline values were within the range 0.3-0.9 mL/cm H2O for compliance and within the range 0.1-0.199 cm H2O/mL per second for resistance, the pulmonary evaluation was initiated. A Buxco pulmonary measurement computer program enabled the collection and derivation of pulmonary values. Starting this program initiated the experimental protocol and data collection. The changes in volume over time that occured within the plethysmograph with each breath were measured via a Buxco pressure transducer. By integrating this signal over time, a measurement of flow was calculated for each breath. This signal, together with the pulmonary driving pressure changes, which were collected using a Sensym pressure transducer (#TRD4100), was connected via a Buxco (MAX 2270) preamplifier to a data collection interface (#""s SFT[3400 and SFT3813). All other pulmonary parameters were derived from these two inputs.
Baseline values were collected for 5 minutes, after which time the guinea pigs were challenged with Ach. Ach was infused intravenously for 1 minute from a syringe pump (sp210iw, World Precision Instruments, Inc., Sarasota, Fla.) at the following doses and prescribed times from the start of the experiment: 1.9 xcexcg/minute at 5 minutes, 3.8 xcexcg/minute at 10 minutes, 7.5 xcexcg/minute at 15 minutes, 15.0 xcexcg/minute at 20 minutes, 30 xcexcg/minute at 25 minutes and 60 xcexcg/minute at 30 minutes. If resistance or compliance had not returned to baseline values at 3 minutes following each Ach dose, the guinea pig""s lungs were inflated 3 times with 4 mL of air from a 10 mL calibration syringe. Recorded pulmonary parameters included respiration frequency (breaths/minute), compliance (mL/cm H2O) and pulmonary resistance (cm H2O/mL per second) (Giles et al., 1971). Once the pulmonary function measurements were completed at minute 35 of this protocol, the guinea pig was removed from the plethysmograph and euthanized by CO2 asphyxiation.
The quantity PD2, which is defined as the amount of Ach needed to cause a doubling of the baseline pulmonary resistance, was calculated using the pulmonary resistance values derived from the flow and the pressure over a range of Ach challenges using the following equation. This was derived from the equation used to calculate PC20 values in the clinic (Am. Thoracic Soc, 2000).       PD    2    =      antilog    ⁡          [                        log          ⁢                      xe2x80x83                    ⁢                      C            1                          +                                            (                                                log                  ⁢                                      xe2x80x83                                    ⁢                                      C                    2                                                  -                                  log                  ⁢                                      xe2x80x83                                    ⁢                                      C                    1                                                              )                        ⁢                          (                                                2                  ⁢                                      R                    0                                                  -                                  R                  1                                            )                                                          R              2                        -                          R              1                                          ]      
where:
C1=Second to last Ach concentration (concentration preceding C2)
C2 =Final concentration of Ach (concentration resulting in a 2-fold increase in pulmonary resistance (RL))
R0=Baseline RL value
R1=RL value after C1 
R2=RL value after C2 
Statistical analysis of the data was performed using a One-Way Analysis of Variance followed by post-hoc analysis using a Bonferroni/Dunn test. A P-value  less than 0.05 was considered significant.
Dose-response curves were fitted with a four parameter logistic equation using GraphPad Prism, version 3.00 for Windows (GraphPad Software, San Diego, Calif.)
Y=Min+(Maxxe2x88x92Min)/(1+10{circumflex over ( )}((log ED50xe2x88x92X)*Hillslope)),
where X is the logarithm of dose, Y is the response (PD2), and Y starts at Min and approaches asymptotically to Max with a sigmoidal shape.
Representative compounds of the invention were found to have significant bronchoprotective activity at time points beyond 24 hours post-dose.